Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

Abstract

The in vivo biotransformations of drugs known to be metabolized by enzymes localized in the endoplasmic reticulum of liver can be greatly altered by diet in humans, as we have shown previously. Steroid hormones also are metabolized extensively by hepatic microsomal enzymes; therefore, we examined the possibility that testosterone and estradiol biotransformations, as assessed with radiolabeled tracer methods, could be influenced by dietary macronutrients. Normal males were fed a high-protein diet for 2 weeks, followed by a high-carbohydrate diet for an additional 2 weeks. The A4-5a-reduction of testosterone was considerably diminished, while the cytochrome P-450-dependent hydroxylation of estradiol at the C2 position was substantially enhanced during ingestion of the high-protein diet as compared with the high-carbohydrate diet. These results indicate that dietary macronutrients can significantly alter major metabolic pathways for testosterone and estradiol in man. The mechanism by which reciprocal changes in the A4-5a-reduction of testosterone and the cytochrome P-450-mediated oxidation of estradiol are produced by diet is not known. Similar changes in steroid A4-5a-reduction and cytochrome P-450-dependent chemical oxidations have been observed in circumstances in which the mixed-function oxidase system in liver is induced by agents such as phenobarbital, hexachlorobenzene, dioxin, and polyhalogenated biphenyls. Thus, the alterations in steroid hormone metabolism produced by dietary macronutrients in man mimic those that can be produced by drugs and environmental chemicals.The oxidative metabolism of drugs can be greatly influenced by specific components of the human diet, as studies from our laboratories have shown (1-8). These studies demonstrated that feeding humans cruciferous vegetables (5), charcoal-broiled beef (6-8), or a high-protein/low-carbohydrate diet (1-4) stimulates the metabolism of certain drugs by the microsomal cytochrome P-450-dependent mixed-function oxidase system. Natural steroid hormones, like many drugs and other foreign chemicals, also undergo biotransformations mediated by microsomal enzymes (9-12); therefore, it was of interest to determine whether the dietary content of protein and carbohydrate could alter the metabolism of such hormones in humans. The major sex steroids, testosterone and estradiol, were chosen for study because cytochrome P-450-dependent oxidation is the principal metabolic fate of the latter compound (12, 13), whereas reduction by a microsomal A4-5a-reductase represents a primary biotransformation for the androgen (14). Thus by changing, in a carefully controlled fashion, the dietary intakes of protein and carbohydrate in the same individuals, the role of specific nutritional factors in determining the metabolic fate of these steroid hormone substrates of microsomal enzymes could be determined. The metabolism of antipyrine also was studied because the effects of protein and carbohydrate in the diet on the oxidative disposition of this cytochrome P-450 subs...

Diet and Breast Cancer

“…Furthermore, a high protein diet considerably diminished 4-ene-5cr-reduction of T and enhanced 2-hydroxylation of E2 (13,14). We could recently confirm that a high dietary protein/carbohydrate ratio is associated with a high urinary excretion of catecholestrogens ( 15).…”

The Influence of Dietary Protein and Carbohydrate on the Principal Oxidative Biotransformations of Estradiol in Normal Subjects*

“…Our results thus indicate that antipyrine oxidation and estrogen 2-hydroxylation are altered in a parallel fashion by changes in the protein to carbohydrate ratio in the human diet. In contrast, the A 4 -5«-reductive metabolism of testosterone was decreased by the same dietary regimen which increased the estrogen oxidation (17).…”

Race and sex influence clearance of nifedipine: Results of a population study

“…37,38 Although certain fruits can decrease intestinal metabolism of drugs, long-term exposure to certain vegetables can also induce enzymes and increase drug clearance. 39,40 In human beings, isocaloric substitution of protein for carbohydrate alters metabolism of steroid hormones and antipyrine, a probe of hepatic metabolism 41 ; and dietary salt has been shown to alter first-pass elimination of quinidine. 42 Dietary factors (such as alcohol, cabbage, brussels sprouts, and grapefruit juice) can alter expression of intestinal cytochrome P450 activity in animals and human beings.…”